Division of Genetics and Metabolism, Department of Paediatrics, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, Singapore, Singapore.
Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Mol Genet Genomic Med. 2024 Jan;12(1):e2285. doi: 10.1002/mgg3.2285. Epub 2023 Sep 23.
Beta thalassemia, related to HBB mutation and associated with elevated hemoglobin A2 (HbA2), is an important genetic hemoglobinopathy with high incidences of disease and carrier rates in Singapore. Carrier screening is essential to facilitate prenatal counseling and testing. However, when individuals with elevated HbA2 do not have an identifiable HBB disease-associated variant, there is ambiguity on risk to their offspring.
We describe a case report of a proband with elevated HbA2, no identifiable HBB disease-associated variant, whose partner was a beta thalassemia carrier. Through clinical HBB gene sequencing, multiplex ligation-dependent probe amplification (MLPA) analysis, as well as targeted Nanopore long read sequencing of selected genes, we performed a complete analysis of HBB including the promoter region, 5'UTR and coding gene sequence, as well as evaluation for potential modifier variants and other rare structural variants.
This process identified that the proband was heterozygous for KLF1:c.544T>C (p.Phe182Leu), a potential functional polymorphism previously known to be associated with benign elevated HbA2 levels. The presence of disease variants in the HBB locus was excluded.
This finding provided clarity and enabled family planning for the proband and her family.
β地中海贫血与 HBB 突变相关，伴有血红蛋白 A2（HbA2）升高，是一种重要的遗传性血红蛋白病，在新加坡的发病率和携带率都很高。携带者筛查对于促进产前咨询和检测至关重要。然而，当 HbA2 升高的个体没有可识别的与 HBB 疾病相关的变异时，其后代的风险存在不确定性。
我们描述了一个 HbA2 升高的先证者的病例报告，没有可识别的与 HBB 疾病相关的变异，其伴侣是β地中海贫血携带者。通过临床 HBB 基因测序、多重连接依赖性探针扩增（MLPA）分析，以及对选定基因的靶向纳米孔长读测序，我们对 HBB 进行了全面分析，包括启动子区域、5'UTR 和编码基因序列，以及评估潜在的修饰变体和其他罕见的结构变体。
这一过程确定先证者为 KLF1:c.544T>C（p.Phe182Leu）杂合子，这是一种先前已知与良性 HbA2 水平升高相关的潜在功能多态性。排除了 HBB 基因座上存在疾病变异。
这一发现为先证者及其家人提供了明确的信息，并为其家庭规划提供了依据。
